Could Head Shape Help Explain Alzheimer's Risk? Researchers Test an Unconventional Idea

Alzheimer's disease tends to begin in one place. Years before memory starts to fail, tangles of a protein called tau gather and cells die in the entorhinal cortex, a structure near the base of the brain. Neuroscientists call the pattern "selective vulnerability": a disease wrecks some regions and cells while leaving their neighbors alone. Explaining why, and how to stop it, is among the field's most sought-after goals.

A new paper in the journal Alzheimer's & Dementia, published this month, offers an unconventional line of inquiry. In a preliminary study, tau buildup in the entorhinal cortex was linked to the progression of Alzheimer's only when that region sat close to the edge of the tentorial incisura, a notch in the brain's outer lining. The finding raises questions the authors themselves describe as unorthodox. Might the repeated mechanical stresses of daily life, combined with a lifetime of gravity's pull, create pressure points in the brain? And could differences in the anatomy of a person's head help explain why some people develop dementia and others do not?

The work comes from Dr. John Crary, a neuropathologist at the Icahn School of Medicine at Mount Sinai in New York, and Frank Provenzano, a neural imaging bioengineer at Columbia University. Crary said the idea "started in hushed tones in neuropathology circles." It also carries an uncomfortable echo: the 19th century's discredited use of head shape to predict personality and justify racism.

Crary's interest grew from his work. He runs a brain bank and has studied chronic traumatic encephalopathy, or CTE, a form of neurodegeneration caused by repeated head trauma. CTE has shown that mechanical forces can trigger toxic tau tangles. Much of what is known about the brain, he notes, comes from autopsies, after the organ has been removed from the skull and mapped out of context. The relationship between skull and brain has been studied in head injuries but largely left untested in neurodegenerative disease.

He had also read a 1958 paper reporting unusual autopsy data in which part of the skull was removed. It showed wide variation in the size of the tentorial notch, the lip of a passage between two compartments of the brain. After an acute injury or stroke, swollen brain tissue can press against the rigid edge of that notch. Crary wondered whether the smaller, cumulative effects of a lifetime of movement might do something similar. "Some people have big ones, some have small ones, some have long ones, some have short ones," he said, adding that he thought this could be a risk factor.

To test it, the team analyzed medical scans from 47 people with mild cognitive impairment who had tau tangles in the vulnerable area. They measured the distance between the hard edge of the notch and the entorhinal cortex. That distance did not predict how much tau was present, and brain architecture alone did not predict who would develop Alzheimer's. But tau in the at-risk region was linked to developing dementia over the following three years only in people with a tight gap between the notch and the cortex.

Both researchers say the small study is a starting point, not a proven case, and hope it prompts follow-up work. The field has long concentrated on amyloid-beta clumps and, more recently, tau. Several drugs that remove amyloid have been approved, but they have given patients limited benefit.

Outside scientists were interested but careful. Dr. Gil Rabinovici, a neurologist at the University of California, San Francisco, who was not involved, called it "really outside the box, which I love," while saying more evidence is needed. David Attwell, a neuroscientist at University College London, called it an "intriguing correlation." He noted that microglia, the cells that clear amyloid-beta, are sensitive to being stretched, but said other factors might also correlate with the distance between the two regions. Michael Yassa, a neurobiologist at the University of California, Irvine, whose lab published a Nature Communications paper last year on the brain's changing shape over a lifetime, described the "slouch of gravity" that compresses the brain in some directions and stretches it in others, with effects more pronounced in older adults with memory impairment. He argued the field remains dominated by ideas dating to 1909.

The hypothesis now needs larger studies to see whether it holds. Even if it does not, researchers say it may still spark new observations.